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x_NeuroGenetics Review > Basic Concepts > Flashcards

Basic Concepts Flashcards

1
Q

What is a locus?

A

Segment of DNA occupying a particular position or location on a chromosome

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2
Q

What are alleles?

A

Alternative variants of a gene

  • Wild type or common allele: single prevailing allele present in the majority of individuals
  • Other versions are variant of mutant alleles that differ from the wild-type because of the presence of a mutation
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3
Q

Define the following:

  • Homozygous
  • Heterozygous
  • Compound heterozygote
A
  • Homozygous: when a person has a pair of identical alleles at a locus
  • Heterozygous (aka “carrier”): when a person has different alleles on both pairs of a chromosome
  • Compound heterozygote (aka “double heterozygote”): 2 different mutant alleles of the same gene are present
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4
Q

What is hemizygous?

A

Male has an abnormal allele for a gene located on the X chromsome and there is no other copy of the gene (neither homozygous nor heterozygous)

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5
Q

Genotype vs. phenotype?

A
  • Genotype: set of alleles that make up his/her genetic constitution; either collectively at all loci or more typically, at a single locus
  • Phenotype: observable expression of a genotype as a morphological, clinical, cellular, or biochemical trait
  • Can be normal or abnormal
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6
Q

How many genes do humans have?

  • Chromosomes?
A
  • About 20,000 genes
  • 46 chromosomes (23 pairs)
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7
Q

Describe the following genetic disorder patterns:

  • Single gene (Menelian)
  • Chromosomal
  • Multifactorial

in terms of:

  • Prevalence
  • Pattern of inheritance
  • Risk to relatives
A

Single gene (Mendelian)

  • Numerous though individually rare
  • Clear pattern of inheritance
  • High risk to relatives

Chromsomal

  • Mostly rare
  • No clear pattern of inheritance
  • Usually low risk to relatives

Multifactorial

  • Common disorders
  • No clear pattern of inheritance
  • Low/moderate risk to relatives
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8
Q

What is penetrance?

A

Percentage of relatives expressing the disorder to any degree, from the most trivial to the most severe

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9
Q

What are different types/expressions of penetrance? Examples?

A

Age dependent penetrance

  • Huntington disease

Incomplete penetrance: not all mutation carriers will manifest the disorder during a natural lifespan

  • Lynch syndrome
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10
Q

What is expressivity?

A

Variation in the severity of a disorder in individuals who have inherited the same disease alleles

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11
Q

What are the different types/expressions of expressivity?

A

- Interfamilial variation: difference in severity between families

- Intrafamilial variation: difference in severity within families carrying the same mutation

  • E.g. tuberous sclerosis
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12
Q

What is mosaicism? Subtypes?

A

Somatic mosaicism:

  • A new mutation arising at an early stage in embryogenesis causing a partial phenotype
  • Ex) segmental NF1

Gonadal/germline mosaicism:

  • A new mutation arising during oogenesis or spermatogenesis may cause no phenotype in the parent but can be transmitted to the offspring
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13
Q

Describe autosomal dominant inheritance

  • Number of mutant alleles
  • Chance of passing to offspring
  • Features of inheritance pattern
A
  • 1 mutant allele is sufficient to cause disease
  • 50% chance of transmission with each pregnancy

Features:

  • Vertical transmission
  • Male-to-male transmission
  • Affected males = affected females
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14
Q

What inheritance pattern is seen here?

A

Typical autosomal dominant

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15
Q

What inheritance pattern is seen here?

A

Non-penetrance of autosomal dominant

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16
Q

What inheritance pattern is seen here?

A

New mutation (of autosomal dominant)

17
Q

What inheritance pattern is seen here?

A

Sex-limited expression (of autosomal dominant)

18
Q

What inheritance pattern is seen here?

A

Gonadal mosaicism

19
Q

Describe autosomal recessive inheritance

  • Number of mutant alleles
  • Features of inheritance pattern
A
  • 2 mutant genes are required to cause disease

Features:

  • Horizontal pattern of affected individuals
  • Males and females equally affected
  • Parents unaffected yet obligate carriers
  • Child of affected persons is (at least) obligate carrier
20
Q

What is the Lyon Hypothesis?

A

One X in female somatic cells undergoes random inactivation

21
Q

Describe sex chromosome inheritance

A
  • Males are hemizygous for genes on the X chromosome
  • All daughters of affected males are carriers
  • 50% of daughters of carrier females are carriers
  • 50% of sons of carrier females are affected
  • All sons of affected males are “normal”; there is no male-male transmission of X linked conditions!
22
Q

Describe the mitochondrial genome

  • Linear vs. circular
  • Number of nucleotides/genes
  • Products
  • Inheritance pattern
A
  • Circular, mtDNA
  • 16,000 nucleotides encoding 13 proteins (many are subunits of protein complexes of the respiratory chain, 2 rRNA genes, and 22 tRNA genes)
  • Almost entire genome is coding sequence
  • Derived from oocyte mitochondria, thus they exhibit MATRILINEAL inheritance
  • Affected female can pass disorder to ALL of her progeny
  • Expression determined by degree of heteroplasmy
23
Q

What is multfactorial/polygenic inheritance?

A

Disorders/traits that result from complex interactions between many or few genes and the environment

  • Although the disorder/trait may be familial, there is NOT a simple mendelian pattern of inheritance
  • Recurrence risks are based on empiric data
24
Q

What does this pedegree show?

A

Multifactorial inheritance

25
Q

Key concept: even without a positive family history we all have risks!

A

Examples, even in “normal” population:

  • 1/30 risk of child being born with some congenital abnormality
  • 1/50 risk of child being born with serious physical or mental handicap
  • 1/8 risk of pregnancy ending with spontaneous abortion
26
Q

In pedigrees, what shapes are used for:

  • Males
  • Females
  • Unknown sex
  • Miscarriage/abortion
A
  • Males: square
  • Females: circle
  • Unknown sex: diamond
  • Miscarriage/abortion: triangle
27
Q

What does a slash through a shape indicate on a pedigree?

A

Deceased individual

28
Q

What is the approach to genetic conditions with the physical exam?

A
  • Head to toe: inspection
  • Facial dysmorphisms (one thing alone may mean nothing)
  • Obvious structural anomalies
  • Fingers/toes
  • Measurement of height, weight, and head circumference
29
Q

What are different forms of genetic evaluation?

A

Chromosome/DNA level:

  • Karyotype
  • FISH
  • Array CGH

Nucleotides

  • Sequencing
  • Single gene/panel
  • Whole exome
30
Q

What can be seen in a karytopye? What conditions?

A
  • Abnormal number
  • Down syndrome (3x21)
  • Klinefelter syndrome (XXY)
  • Turner (XO)
  • Balanced translocation
  • Big deletions/duplications
31
Q

What is array CGH?

  • Indications for it?
A
  • Array Comparative Genomic Hybridization (Array CGH) allows for the detection of a large number of DNA copy number changes (gain/loss)
  • Indications include: dysmorphic features; unexplained intellectual disability; autism spectrum disorder and/or multiple congenital anomalies
32
Q

What is the process/mechanism of chromosomal microarray (CMA) or array CGH?

  • What does Cy3/Cy5 > 1 indicate? < 1?
A
  • Label pt DNA with Cy3 (green) and control with Cy5 (red)
  • Mix should appear yellow
  • Hybridize DNA to genomic clone microarray
  • Analyze Cy3/Cy5 fluorescence ratio of patient to control
  • Cy3/Cy5 > 1: duplication (more green)
  • Cy3/Cy5 < 1: deletion (more red)
33
Q

When is single gene testing helpful?

  • Benefits?
A
  • Phenotype and other findings clearly point to one disorder that is associated with one gene
  • Ex) Marfan syndrome is associated only with the gene FBN1
  • High clinical sensitivity
  • Minimal risk of Variants of uncertain significance (VUS)
34
Q

When are gene panels helpful?

  • Benefits?
A
  • Increases analytical sensitivity to DNA diagnostic testing
  • Simplifies the decision making process for the ordering physician
  • Number of genes for the same or similar clinical indications vary among different labs
  • Is “more” better?
  • Genes with a strong association are certainly included
  • Genes associated with disorders that have overlapping phenotypes with those of the primary disorders are included for differential diagnosis
35
Q

What is whole exome sequencing used for?

A

To analyze the exons or coding regions of thousands of genes simultaneously using next-generation sequencing techniques

  • There are ~ 180,000 exons in the human genome, which represent about 3% of the genome and are arranged in about 22,000 genes
36
Q

What is exome sequencing used for?

A

Exome sequencing is now the most commonly used tool for Mendelian disease gene discovery

  • Diagnostic yield of 25%
  • Significant cost-benefit for patients who remain undiagnosed after a few traditional appraoches

x_NeuroGenetics Review (38 decks)

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